Cryptococcus neoformans meningitis occurs in 5-13% of individuals with aids in the United States. As an initial infection it is associated with the worst prognosis of all AID-associated infections. This project seeks to establish a potential role for antibodies in immunity to human cryptococcosis by demonstrating that anti-cryptococcal polysaccharide antibodies can be identified in individuals who have been expose to C. Neoformans. Although the traditional view is that immunity to cryptococcosis is cell mediated, numerous studies have demonstrated the importance of antibody-mediated processes. The presence of anti- cryptococcal antibodies in HIV positive individuals is difficult to predict since B cell defects that impair responses to encapsulated bacteria and polyclonal stimulation of B cells have both been noted in HIV infection. The basis of serologic studies to be performed is an antigen-based ELISA. Serotype reactivity of HIV positive and HIV negative individuals will be determined on purified cryptococcal polysaccharide-coated ELISA plates. Associations between HIV status and anti-cryptococcal antibody titer, antibody isotype, IgG subclass, and antibody specificity will be examined in adults and children. Murine anti-cryptococcal monoclonal antibodies will be used in competition experiments with human sera in order to determine whether human anti- cryptococcal antibodies recognize the same epitopes as existing protective murine antibodies. Affinity chromatography and isoelectric focusing will be utilized to further characterize human anti-cryptococcal antibody responses. Preliminary studies of human anti-cryptococcal polysaccharide antibodies with a rabbit anti-idiotypic reagent that recognizes a protective murine anti-cryptococcal monoclonal have demonstrated a cross-reactive idiotype in human and murine anti- cryptococcal polysaccharide antibody response. Human anti-idiotypic reagents will be generated in addition to human monoclonals to further prove the nature of the human anti-cryptococcal antibody response. Two monoclonal antibodies have already been isolated by EBV transformation of human peripheral lymphocytes. Nucleic acid sequences of the monoclonal will be determined to elucidate the molecular genetic structure of human anti-cryptococcal antibodies and to evaluate the nature of variable region gene element utilization in their derivation. Correlates between serologic parameters or antibody structure and the development or prognosis of C. neoformans meningitis in HIV positive individuals would represent a powerful rationale for the use of antibody proposal may provide new, urgently needed reagents for the therapy of cryptococcosis as will as new insights into human C. neoformans immunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS and Related Research Study Section 5 (ARRE)
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Szymczak, Wendy A; Sellers, Rani S; Pirofski, Liise-anne (2012) IL-23 dampens the allergic response to Cryptococcus neoformans through IL-17-independent and -dependent mechanisms. Am J Pathol 180:1547-59
Casadevall, Arturo; Pirofski, Liise-Anne (2011) A new synthesis for antibody-mediated immunity. Nat Immunol 13:21-8
Pirofski, Liise-Anne (2010) Why antibodies disobey the Hippocratic Oath and end up doing harm: a new clue. J Clin Invest 120:3099-102
Subramaniam, Krishanthi S; Datta, Kausik; Marks, Matthew S et al. (2010) Improved survival of mice deficient in secretory immunoglobulin M following systemic infection with Cryptococcus neoformans. Infect Immun 78:441-52
Subramaniam, Krishanthi S; Datta, Kausik; Quintero, Eric et al. (2010) The absence of serum IgM enhances the susceptibility of mice to pulmonary challenge with Cryptococcus neoformans. J Immunol 184:5755-67
Subramaniam, Krishanthi; Metzger, Brian; Hanau, Lawrence H et al. (2009) IgM(+) memory B cell expression predicts HIV-associated cryptococcosis status. J Infect Dis 200:244-51
Pirofski, Liise-anne; Casadevall, Arturo (2009) Rethinking T cell immunity in oropharyngeal candidiasis. J Exp Med 206:269-73
Ritter, M L; Pirofski, L (2009) Mycophenolate mofetil: effects on cellular immune subsets, infectious complications, and antimicrobial activity. Transpl Infect Dis 11:290-7
Datta, Kausik; Lees, Andrew; Pirofski, Liise-anne (2008) Therapeutic efficacy of a conjugate vaccine containing a peptide mimotope of cryptococcal capsular polysaccharide glucuronoxylomannan. Clin Vaccine Immunol 15:1176-87
Datta, Kausik; Pirofski, Liise-anne (2006) Towards a vaccine for Cryptococcus neoformans: principles and caveats. FEMS Yeast Res 6:525-36

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